Medical Specialties Commons^™

Cells And Networks In Flux: Rethinking Ontogenesis And Pathogenesis, Mark L. Tykocinski

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That …

Selective Loss Of Primary Cilia And Neurotrophic Signaling In G51d Α-Synuclein Mice Highlights A Common Pathway To Parkinson’S Disease, Yu-En Lin, Ebsy Jaimon, Youngdoo Kim, Annabeth Loftman, Aaran Vijayakumaran, Benjamin D W Belfort, Claire Y Chiang, Benjamin R Arenkiel, Huda Y Zoghbi, Suzanne R Pfeffer

Duncan NRI Faculty and Staff Publications

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform …

Hemodynamic Characterization Of Cardiac Dysfunction After Traumatic Brain Injury Using A Controlled Cortical Impact Model In Male Rats, Preston So, Amit Iyengar, Noah Weingarten, Mrinal Patel, Jessica Dominic, Andrew Belec, Joyce Ho, Samuel Shin, Pavan Atluri

Division of Cardiology Faculty Papers

Traumatic brain injury (TBI) is associated with cardiovascular dysfunction that worsens clinical outcomes, yet the underlying mechanisms are poorly under stood. Clinical studies are limited by heterogeneity, highlighting the need for con trolled experimental models. Controlled cortical impact (CCI) provides precise control of injury severity, and invasive pressure- volume (PV) loop analysis allows detailed hemodynamic assessment. Adult male Wistar rats underwent sham op eration or mild or severe CCI- induced TBI. PV- loop assessment and transtho racic echocardiography were performed at 8 or 24 h after TBI or sham. Serum epinephrine (EPI) and norepinephrine (NE) were quantified by ELISA. At …

Translational Reading Frame Predicts The Pathogenicity Of C-Terminal Frameshift Deletions In Mecp2, Jacky Guy, Elena Hein, Beatrice Alexander-Howden, Timur Von Bock Und Polach, Tricia Mathieson, Benjamin P Kleinstiver, Huda Y Zoghbi, Adrian Bird

Duncan NRI Faculty and Staff Publications

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline …

Non-Enzymatic Hepatic Abhd6 Interacts With Akt-Foxo1 Axis To Regulate Metabolic Health, Guannan Li, Laurence T Maeyens, Jiyuan Yin, Jan-Bernd Funcke, Chanmin Joung, Ruizhen Li, Ziying Xu, Ting Wu, Xin Li, Nisi Jiang, Mbolle Ekane, Maria Paula Lopez, Pengju Cao, Sijia He, Adam B Salmon, S R Murthy Madiraju, Marc Prentki, Juli Bai, James F Nelson, Xianlin Han, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin …

Hyperadhesive Von Willebrand Factor Contributes To Pathogenesis Of Preeclampsia, Yajuan Wang, Chenyu Wang, Katie L Houck, Xiaoli Gao, Yuanyuan Chen, Xin Xu, Xue Zhao, Miguel A Cruz, Shu Zhang, Chester Q Li, Fengxia Xue, Min Li, Swati Shree, Jing-Fei Dong, Cha Han

Children’s Nutrition Research Center Staff Publications

Background: Preeclampsia is the most common complication of pregnancy, significantly affecting maternal and fetal health, and is characterized by placental and systemic endotheliopathy. Patients with preeclampsia have elevated levels of VWF (von Willebrand Factor), which is associated with poor clinical outcomes. However, whether VWF serves as a marker for endotheliopathy or contributes to the pathogenesis of preeclampsia remains poorly understood.

Methods: We investigated the role of hyperadhesive VWF in the development of preeclampsia by studying patients, evaluating mouse models, and performing in vitro experiments.

Results: We show that patients develop VWF- and fibrin-rich thrombosis in the placenta and have significantly …

Hippo Signaling Regulates Cuticle Pigmentation And Dopamine Metabolism In Drosophila, Shelley B Gibson, Samantha L Deal, Ye-Jin Park, Bo Sun, Yanyan Qi, Jung-Wan Mok, Hyung-Lok Chung, Hongjie Li, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Pigmentation plays multiple important roles in development, physiology and evolution. Melanization of the insect cuticle requires dopamine as a precursor of melanin and involves key enzymes in dopamine biosynthesis including Tyrosine hydroxylase (TH) and Dopa decarboxylase (Ddc). Some studies have hinted that disruption of the evolutionarily conserved Hippo signaling pathway, which has been primarily studied in the context of tissue growth, may lead to changes in cuticle pigmentation in the fruit fly Drosophila melanogaster. However, to our knowledge, there have not been any systematic investigations into their potential mechanistic links. In this study, we identified that all genes that comprise …

Neural-Immune-Cardiovascular Axis: From Mechanistic Crosstalk To Therapeutic Targets In Cardiovascular Disease, Junkang Cheng, Shuang Gao, Haowei Zhang, Wei Gao, Zeyuan Mei, Xiaoling Liu, Jocelyn Gao, Chenghu Guo, Guipeng An

Student Papers, Posters & Projects

The neural-immune-cardiovascular axis represents an emerging and highly integrated physiological and pathophysiological concept, describing a complex bidirectional communication network between the nervous, immune, and vascular systems. This review systematically examines the pivotal role of this axis in maintaining cardiovascular homeostasis and in the pathogenesis of cardiovascular diseases. We first provide an overview of the fundamental signaling pathways between the components of this axis. Subsequently, we delve into the specific crosstalk mechanisms within the axis in the context of major cardiovascular conditions, including atherosclerosis, hypertension, and heart failure. A central focus is placed on critically evaluating the potential therapeutic targets and …

Combining Menin And Mek Inhibition To Target Poor Prognosis Kmt2a-Rearranged Ras Pathway-Mutant Acute Myeloid Leukemia., Nastassja Scheidegger, Constanze Schneider, Gabriela Alexe, Yi-Cheng Wang, Todd A. Alonzo, Allen Basanthakumar, Wallace A. Bourgeois, Julia Dudkiewicz-Garbicz, Delan Khalid, Lucy A. Merickel, Jennifer A. Perry, Rhonda E. Ries, Silvi Salhotra, Audrey Taillon, Alan S. Gamis, Richard Aplenc, Marian H. Harris, Mark Wunderlich, Scott A. Armstrong, Jessica A. Pollard, Soheil Meshinchi, Yana Pikman, Kimberly Stegmaier

Manuscripts, Articles, Book Chapters and Other Papers

KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of acute myeloid leukemia (AML) cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission rate, poor event-free survival and overall survival (OS), and early relapses. Given the …

Slc Transporter-Mediated Functional Imaging In Cancer Diagnosis, Lumeng Zhang, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Functional imaging has become an important approach for evaluating tumor physiology in vivo beyond morphologic assessment. Radiotracers used for cancer imaging are designed to mimic endogenous substrates or substrate analogues, and their accumulation can depend on membrane transport, intracellular metabolism, and clearance from normal tissues. Specifically, SLC transporters contribute to tracer uptake and signal formation, linking transporter activity with measurable imaging signals in cancer. While [18F]FDG PET/CT remains the most widely used example of transporter-associated metabolic imaging, SLC transporter-mediated imaging strategies have been developed to assess amino acid transport, sodium-dependent glucose uptake, redox metabolism, lactate exchange, nucleoside metabolism, choline metabolism, …

Na-Gst-1 Adsorbed On Alhydrogel Co-Administered With Different Toll-Like Receptor Agonists In Hookworm-Naive Adults Using A Controlled Human Infection Model In The Usa: A Phase 2, Double-Blind, Randomised Controlled Trial, Caroline K Dirosato, Elissa M Malkin, Sean M Lee, Guacyara Erwin, Lara Hoeweler, Larissa Scholte, Maria Elena Bottazzi, David I Pritchard, Peter J Hotez, Jeffrey M Bethony, David J Diemert

Faculty, Staff and Students Publications

Background: Necator americanus glutathione S-transferase-1 (Na-GST-1) performs a crucial enzymatic step in hookworm blood feeding and is a leading target for vaccine development. Phase 1 trials in Brazil, Gabon, and the USA of recombinant Na-GST-1 adsorbed on Alhydrogel (Na-GST-1/Al), co-administered with or without AP 10-701 (Toll-like receptor [TLR] 4 agonist) or CpG 10104 (TLR9 agonist), showed the vaccine was well tolerated, safe, and immunogenic. A controlled human hookworm infection (CHHI) model was previously developed to evaluate the effect of candidate hookworm vaccines on infection. We aimed to assess the effect of vaccination with three different Na-GST-1 vaccine formulations on subsequent …

Helminth-Infected Mozambican Children With Malaria Have Increased Anaemia, Cytokines And Helminth-Specific Antibodies, Inocência Cuamba, Rebeca Santano, Berta Grau-Pujol, Marta Vidal, Anélsio Cossa, Chenjerai Jairoce, Rojelio Mejía, José Muñoz, Ruth Aguilar, Bin Zhan, Augusto Nhabomba, Gemma Moncunill, Carlota Dobaño

Faculty, Staff and Students Publications

Owing to their overlapping geographical distribution and the consequent occurrence of coinfections, several studies have evaluated the impact of helminth infections on malaria immune responses and clinical outcomes. However, little has been reported on how malaria coinfection affects anthelmintic responses in children harbouring worm infections. We therefore aimed to assess the impact of malaria coinfection on helminth-related clinical and immune outcomes in children. Here, we measured in plasma the levels of 30 cytokines, total IgE, and helminth-specific IgM, IgA, IgG, IgG1-4, and IgE antibodies to a panel of 11 helminth antigens by Luminex. Samples were obtained from 441 children aged …

Proteogenomics Of Hypertrophic Cardiomyopathy Reveals Subtype-Specific Therapy, Ke Ma, Jie Yang, Hongchang Guo, Ping Li, Xiaowei Li, Zhujun Dong, Jing Zhang, Congcong Zhang, Pengli Yang, Chongpei Hua, Shuolin Zhu, Guoqing Li, Jianchao Zhang, Ningyu Ding, Jizheng Wang, Xin-Liang Ma, Zhuofeng Lin, Jianzeng Dong, Yang Li, Yulin Li

Department of Emergency Medicine Faculty Papers

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with diverse prognosis. The underlying mechanisms remain unknown, resulting in limited risk stratification and therapeutic strategies. This study aimed to elucidate molecular subtypes of HCM through integrated proteogenomic analysis and explore subtype-specific therapeutic strategies.

METHODS: We conducted an integrated proteogenomic analysis of 132 patients with HCM using myocardial samples, incorporating whole-exome sequencing, RNA sequencing, and proteomics. Unsupervised clustering was used to identify HCM subtypes, which were validated in heart tissues and human induced pluripotent stem cell-derived cardiomyocytes from 2 independent HCM subsets. Subtype-specific signatures and pathways were explored, and their causal link …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Yong Du, Li Yang, Hui Dai, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Folr1-Targeted Actinium-225-Based Alpha-Particle Therapy Eliminates Ovarian Cancer, Neetu Singh, Esther Need, Ayden Berndt, Matthew Goff, Lydia J. Wilson, Firas Mourtada, Feng Guo, Tara Mastren, Taslim Al-Hilal, Anil K. Sood, Amit Maity, Scott C. Miller, Satoshi Minoshima, Shreya Goel, Sixiang Shi

Department of Radiation Oncology Faculty Papers

Despite the advancement in therapies, ovarian cancer treatment is challenging because of poor prognosis and high relapse associated with acquired resistance. Emerging targeted alpha particles, particularly actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. Here, we describe a successful example of folate receptor 1 (FOLR1)–targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal positron emission tomography imaging demonstrated high tumor-specific uptake of αFOLR1 (anti-FOLR1 antibody) in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy, achieving marked tumor regression, 80% survival, and 40% complete tumor elimination. The therapy resulted in tumor-specific double-stranded DNA damage, and …

Intrathecal (G4c2)149 Delivery In C9orf72-Deficient Mice Yields Mild Motor Dysfunction And Als/Ftd Pathological Hallmarks, Katelyn Russell, Amelia Shahrabi, Suleyman Akerman, Matthew D. Byrne, Jeffrey Rothstein, Davide Trotti, Brigid Jensen, Aaron Haeusler

Farber Institute for Neuroscience Faculty Papers

A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity …

Hp1bp3 Loss Links Chromatin Reorganization To Metabolic Vulnerability In Glioma, Brittney Lozzi, Taylor A Gatesman, Pushan Dasgupta, Debosmita Sardar, Yeunjung Ko, Chenyu Mao, Hsiao-Chi Chen, Rachel N Curry, Dongjoo Choi, Carrie A Mohila, Melissa L Bondy, Ganesh Rao, Marco Gallo, Sameer Agnihotri, Benjamin Deneen

Duncan NRI Faculty and Staff Publications

High-grade gliomas (HGGs) are aggressive brain tumors with poor prognosis, driven in part by metabolic and epigenetic adaptations. Methionine metabolism supports HGG growth by supplying S-adenosylmethionine for methylation reactions, yet how nutrient availability influences chromatin organization in HGG remains incompletely understood. Using an immunocompetent mouse model of HGG, we found that dietary methionine restriction reduced tumor proliferation, extended survival, and induced partial nuclear inversion. We identified Hp1bp3 as a key regulator of tumor growth that functions by interacting with nuclear tethering proteins to mediate chromatin reorganization. Loss of Hp1bp3 results in the upregulation of histone demethylases leading to selective depletion …

Notch1 Acts As A Tumor Suppressor That Induces Early Differentiation In Head And Neck Cancer, Chenfei Huang, Shhyam Moorthy, Qiuli Li, Kazi M Ahmed, Kalil Saab, Defeng Deng, Jiping Wang, Xiayu Rao, Jiexin Zhang, Yuanxin Xi, Jing Wang, Zhiyi Liu, Noriaki Tanaka, David A Wheeler, Eve Shinbrot, Rami Saade, Curtis R Pickering, Tong-Xin Xie, Adel K El-Naggar, Abdullah A Osman, Kunal Rai, Patrick A Zweidler-Mckay, John V Heymach, Lauren A Byers, Faye M Johnson, Vlad C Sandulache, Jeffrey N Myers, Pedram Yadollahi, Mitchell J Frederick

Faculty, Staff and Students Publications

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early …

Disease-Causing Mfn2 Mutants Impair Mitochondrial Fission Dynamics By Distinct Drp1 Dysregulation, Daniel Lagos, Pamela R. De Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular …

Loss Of Mct1 Mediated Lactate Uptake Causes Delayed Endplate Maturation And Intervertebral Disc Degeneration, Maria Tsingas, Konstantinos Tsingas, Mei Smyers, Wujuan Zhang, Aaron R. Goldman, Eulisa Lawrence, John A. Collins, Makarand V. Risbud

Department of Orthopaedic Surgery Faculty Papers

During skeletal growth, it is thought that the lactate secreted by the glycolytic nucleus pulposus (NP) cells exits the intervertebral disc into circulation via endplates. Our current studies challenge this long-held notion. Mice with early postnatal, endplate, and annulus fibrosus-specific deletion of lactate importer, MCT1, exhibited disc degeneration characterized by NP cell loss and pronounced endplate structural changes. Using metabolic and transcriptomic approaches, we demonstrate that MCT1 loss inhibits endplate chondrocyte differentiation and that lactate serves both as a crucial TCA metabolite and promotes protein and histone lactylation and gene expression. These findings suggest that during skeletal growth, NP-derived lactate …

Comprehensive Proteogenomic Characterization Reveals Clinically Relevant Molecular Subtypes Associated With Medulloblastoma Progression, Seong-Min Park, Kyung-Hee Kim, Jong Hyuk Yoon, Fulvio D'Angelo, Seung Ah Choi, Chan Il Kim, Harim Koo, Seungmin Park, Hyondeog Kim, Sreeja Sundara Raj, Sung Soo Kim, Ae Kyung Park, Eun Jung Koh, Seong-Ik Kim, Yu-Mi Shim, Lee Kwang-Hoon, Eric Eunshik Kim, Ji Hoon Phi, Yeon Suk Jo, Do Hyun Nam, Daehee Hwang, Do Young Hyeon, Sunghyun Huh, Hyung Joon Kwon, Seokjun Ha, Sanha Park, Hyeji Shin, Jeong Taik Kwon, Heon Yoo, Ho-Shin Gwak, Michael D Taylor, Bong Jin Park, Jason K Sa, Youngwook Kim, Antonio Iavarone, Sung-Hye Park, Seung-Ki Kim, Jong Bae Park

Faculty, Staff and Students Publications

Current treatment strategies for medulloblastoma remain ineffective owing to extensive tumor heterogeneity. We generated five platforms of omics data including liquid chromatography and mass spectrometry-based proteome and performed integrated multi-omic characterization to improve the conventional molecular classification of medulloblastoma. We identified seven refined distinct subtypes. The sonic hedgehog (SHH) group was reclassified into two subgroups, SHHα and SHHβ, whereas group 4 was divided into three subgroups, G4α, G4β, and G4γ. SHH and group 4 subtypes exhibit two distinct neuronal differentiation trajectories: granular neuron and unipolar brush cell differentiation (SHHβ and G4γ, respectively), both of which associated with more favorable clinical …

Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy And Phenotypic Expansions, Sarah Araji, Xiaonan Zhao, Jill A Rosenfeld, Seema R Lalani, Daryl A Scott

Faculty, Staff and Students Publications

Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). A molecular cause is not identified in the majority of individuals with DWM+. This is due, in part, to uncertainty regarding optimal testing strategies and an incomplete understanding of the genetic causes of DWM+. In this study, we analyzed clinical exome sequencing (cES) data from 91 individuals with DWM+ to determine …

Development Of A Second-Generation Rarα Selective Antagonist As An Orally Bioavailable, Effective, Safe, And Reversible Male Contraceptive, Rui Shi, Kristen John, Xuan Qin, Ehfazul Haque, Taimeng Liang, Narsihmulu Cheryala, Feng Li, Henry L Wong, Gunda I Georg

Faculty, Staff and Students Publications

We report the design and SAR studies of benzopyran-, benzofuran-, and benzothiophene-derived inhibitors of the retinoic acid receptor alpha (RARα) for male contraception. SAR studies identified critical features influencing activity, such as the optimal positioning of antagonism moieties and substituents, leading to the discovery of (S)-4-(5-(2,8-dimethyl-5-(p-tolyl)-2H-chromen-3-yl)-1H-pyrrol-2-yl)­benzoic acid (compound 23). Compound 23 is a highly potent RARα inhibitor (IC50 = 0.051 nM) with excellent selectivity (>1650-fold over RARβ and >1960-fold over RARγ) and ADMET properties. Compound 23 is orally bioavailable and reduces sperm counts in mice for a full male contraceptive effect …

Cd11c+ Cd8 T Cells Cause Ifn-Γ-Dependent Autoimmune Neuroinflammation That Is Restrained By Pd-1 Signaling, Daniel Hwang, Gholamreza Azizi, Larissa Lumi Watanabe Ishikawa, Maryam S. Seyedsadr, Arin Cox, Soohwa Jang, Ezgi Kasimoglu, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric

Department of Neurology Faculty Papers

In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known about the role of CD8 T cells in MS, partly due to the prevalent use of experimental autoimmune encephalomyelitis (EAE) models mediated by CD4 T cells, which have limited involvement of CD8 T cells. Importantly, MS and EAE differ in both their distribution of CNS lesions and neurologic deficits, indicating differences in CNS inflammation. MS lesions are more commonly found in the brain, whereas EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in …

Volume Electron Microscopy Reveals Heterogeneity Of The Hemostatic Response In Veins And Arteries, Maurizio Tomaiuolo, Meghan E. Roberts, Jenna R. Severa, Christopher D. Mansi, Brenna B. Y. Mathers, Anna Mannix, Trace A Christensen, Lawrence F Brass, Talid Sinno, Timothy J. Stalker

Cardeza Foundation for Hematologic Research

Intravital imaging studies have provided insights into the spatial and temporal variations of platelet activation and thrombin generation that occur during hemostasis; however, these studies are generally limited to small vessels due to the practical limitations of imaging in thicker tissues. Recent advances in cleared tissue fluorescence imaging as well as volume electron microscopy (vEM) coupled with machine learning-based image segmentation provide an opportunity for analysis of the 3-dimensional structure of complex tissues. We utilized these technologies to examine hemostatic plugs from murine jugular veins and carotid arteries to investigate the spatial distribution of platelet activation and biochemical responses in …

Progressive Cardiac Phenotypes And Reduced Reversibility From Long-Term Cugexp Rna Expression In A Dm1 Mouse Model, Rong-Chi Hu, Mohammadreza Tabary, Xander Ht Wehrens, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic, with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUGexp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of …

Genetic Analysis Of The X-Linked Adrenoleukodystrophy Gene Abcd1 In Drosophila Uncovers A Conserved Phenotype, Joshua Manor, Sharayu V Jangam, Hyung-Lok Chung, Pranjali Bhagwat, Jonathan C Andrews, Hillary Chester, Shu Kondo, Saurabh Srivastav, Juan Botas, Ann B Moser, Suzette M Huguenin, Michael F Wangler

Duncan NRI Faculty and Staff Publications

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with the age of onset varying, sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that …

Purine Metabolic Adaptation Protects The Endothelium From Disturbed Flow-Induced Dna Damage And Atherosclerosis, Qian Ma, Yongfeng Cai, Zhidan Zhang, Dingwei Zhao, Yuan Zhao, Peishan Xu, Tammy Lu, Wendy Zhang, Qiuhua Yang, Yaqi Zhou, Varadarajan Sudhahar, Tohru Fukai, Hanjoong Jo, Yiming Xu, Yuqing Huo

Faculty, Staff and Students Publications

Despite effective lipid-lowering therapies, atherosclerosis continues to be a leading cause of death, with considerable residual cardiovascular risk. Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which induces genomic stress, endothelial injury, and barrier dysfunction. Hemodynamic forces are known to reprogram endothelial metabolism, but the role of de novo purine synthesis (DNPS), which supplies nucleotides for genome maintenance and whose terminal steps are catalyzed by the bifunctional enzyme ATIC, remains undefined in atherosclerosis. By integrating bulk and single-cell multiomics with in vitro flow systems and in vivo models, we show that d-flow upregulates DNPS and ATIC …

Antibody-Drug Conjugates Beyond Her2 In Non-Small Cell Lung Cancer (Nsclc): Mechanisms, Emerging Targets, And Future Directions., Ahmed Ismail, Aakash Desai, George R Simon, Yanis Boumber

Oncology Articles

Antibody-drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of …

Ixodid And Flea Infestations And Associated Bacteria On Two Sympatric Felid Species In South Texas, Allan T Showler, Hilary Swarts, Maya Murry, Alisa Nelson, Alexander R Kneubehl, Sarah M Gunter

Faculty, Staff and Students Publications

Ixodid ticks and fleas parasitize wild felids and can transmit pathogens of veterinary and public health concern. We identified ixodid and flea species collected from sympatric South Texas bobcats, L. rufus, and ocelots, L. pardalis. Greater diversities of ixodids were found on both felids than in previous reports, with seven species in three genera on L. rufus and six species in three genera on L. pardalis. We report first findings of tropical horse tick, Dermacentor nitens, on L. rufus in Texas, and Ixodes keiransi on both felids in Texas. Although false cayenne tick, Amblyomma tenellum, nymphs were the most abundant …